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Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6544-52. doi: 10.1073/pnas.1518007112. Epub 2015 Oct 12.

A basal stem cell signature identifies aggressive prostate cancer phenotypes.

Author information

  • 1Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095;
  • 2Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064;
  • 3Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064;
  • 4Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095;
  • 5Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA 95064; Department of Biomolecular Engineering, University of California, Santa Cruz, CA 95064; owenwitte@mednet.ucla.edu jstuart@ucsc.edu.
  • 6Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095 owenwitte@mednet.ucla.edu jstuart@ucsc.edu.

Abstract

Evidence from numerous cancers suggests that increased aggressiveness is accompanied by up-regulation of signaling pathways and acquisition of properties common to stem cells. It is unclear if different subtypes of late-stage cancer vary in stemness properties and whether or not these subtypes are transcriptionally similar to normal tissue stem cells. We report a gene signature specific for human prostate basal cells that is differentially enriched in various phenotypes of late-stage metastatic prostate cancer. We FACS-purified and transcriptionally profiled basal and luminal epithelial populations from the benign and cancerous regions of primary human prostates. High-throughput RNA sequencing showed the basal population to be defined by genes associated with stem cell signaling programs and invasiveness. Application of a 91-gene basal signature to gene expression datasets from patients with organ-confined or hormone-refractory metastatic prostate cancer revealed that metastatic small cell neuroendocrine carcinoma was molecularly more stem-like than either metastatic adenocarcinoma or organ-confined adenocarcinoma. Bioinformatic analysis of the basal cell and two human small cell gene signatures identified a set of E2F target genes common between prostate small cell neuroendocrine carcinoma and primary prostate basal cells. Taken together, our data suggest that aggressive prostate cancer shares a conserved transcriptional program with normal adult prostate basal stem cells.

KEYWORDS:

RNA-seq; basal cell; neuroendocrine prostate cancer; prostate cancer; stem cell signature

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PMID:
26460041
PMCID:
PMC4664352
DOI:
10.1073/pnas.1518007112
[PubMed - indexed for MEDLINE]
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